Throughout this application various publications are referred to by number or name in parentheses. The disclosures of these publications, as well as all patents, patent application publications and books cited herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Hypoxia can cause problem responses in multiple body systems, including the pulmonary system and the central nervous system.
Pulmonary hypertension (PH) is a devastating disease associated with progressive hypoxemia, right ventricular failure, and a mortality rate of around 50% within three years of diagnosis (1). Pulmonary hypertension can occur in association with chronic lung disorders, and in these cases hypoxia plays a pivotal role in the pulmonary hypertension etiology. Hypoxia induces pulmonary vessel constriction and persistent hypoxia results in pulmonary vascular remodeling involving proliferation of endothelial cells, smooth muscle cells (SMC), and fibroblasts, resulting in vessel wall thickness and vessel narrowing (2, 3). Pulmonary vascular remodeling permanently increases pulmonary circulation resistance, leading to right ventricular failure, decreased left ventricular preload and reduced cardiac output. Pulmonary vascular remodeling also causes mismatch of the blood flow and the ventilation (V/Q), which, along with decreased cardiac output and possible cardiac shunt, leads to further hypoxia. Rapid progression of pulmonary hypertension symptoms may be due in part to its cyclical nature. Thus, pulmonary hypertension can be initiated by hypoxia, itself causes hypoxia, and hypoxia in turn exacerbates pulmonary hypertension. Although the pathogenesis remains to be clarified, the current evidence suggests that hypoxia-induced pulmonary vascular remodeling is a chronic inflammatory response, and inflammatory cell proliferation plays a key role in this process (2, 4).
As is well known in the art, hypoxia also causes problem responses and pathologies in other body systems. For example, hypoxia causes regional changes in the brain including neurogenesis, hippocampal atrophy, transcriptional factor upregulation, and altered protein expression. These changes are associated with impaired sleep quality, mental performance, productivity, and general well-being, among other central nervous system complications.
Macrophage migration inhibitory factor (MIF) is a potent proinflammatory cytokine involved in both chronic and late stage acute inflammation (5), and it has been shown previously that the lungs can be a major source of this inflammatory protein (6). MIF can increase proliferation of several cell types including those relevant to the vasculature, i.e. fibroblasts (7-12), endothelial cells (13), and SMCs (14, 15). Hypoxia is known to induce MIF expression in certain systems through the hypoxia-inducible factor-1 alpha (HIF-1α) pathway (16-20). Furthermore, MIF amplifies hypoxia-induced HIF-1α stabilization in certain systems, leading to a positive feedback and induction of further MIF and expression of other HIF-1 related factors (18, 21).
Current therapies for pulmonary hypertension and other pathologies associated with hypoxia are limited. There exists a need for new therapeutics for the treatment of pulmonary hypertension and also for other consequences of hypoxia.